Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Treatment with decitabine, a cytidine analog, then midostaurin, a multi-target protein kinase
inhibitor (PKI), may stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth.

Inclusion Criteria:

- Newly-diagnosed acute myeloid leukemia (AML) per the World Health Organization [WHO]
2008 classification [except t (15; 17)], including:

- De novo AML

- Secondary AML

- Secondary AML arising from previously-diagnosed myelodysplastic syndromes (MDS)
treated with deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) (ie,
decitabine or azacitidine)

- FLT3-ITD mutation confirmed in bone marrow aspirate

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
limit of normal (ULN)

- Serum bilirubin ≤ 2.5 ULN

- Serum creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 50 mL/min

- Ejection fraction ≥ 50% by echocardiogram

- Unwillingness or inability to receive conventional chemotherapy

- Ability to understand and the willingness to sign a written informed consent document

- Ability to adhere to the study visit schedule and other protocol requirements

- Life expectancy > 2 months

Exclusion Criteria:

- Receiving concomitant treatment with other anti-neoplastic agents (EXCEPTION:
hydroxyurea). Prior treatment with DNMTi therapy (ie, decitabine or azacitidine) for
MDS is allowed

- Received anti-neoplastic treatment within 4 weeks prior to enrollment (EXCEPTION:
hydroxyurea)

- Received any surgical procedure, excluding central venous catheter placement or other
minor procedures (eg, skin biopsy) within 14 days of study day 1

- Received any investigational agent within 4 weeks prior to enrollment

- Previous or current history of a myeloproliferative disease

- Known active central nervous system (CNS) malignancy

- Any other known disease (except carcinoma in-situ), concurrent severe and/or
uncontrolled medical condition which could compromise participation in the study (eg,
uncontrolled diabetes; cardiovascular disease including congestive heart failure;
myocardial infarction within 6 months with poorly controlled hypertension; chronic
renal disease; active uncontrolled infection)

- Active opportunistic infection or treatment for opportunistic infection within 4 weeks
of first day of study drug dosing

- Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active
viral hepatitis

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of midostaurin

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to midostaurin and/or decitabine

- Impaired cardiac function including any of the following:

- Screening electrocardiogram (ECG) with a corrected QT interval (QTc) > 450 msec

- Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm)

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Patients with myocardial infarction or unstable angina < 3 months prior to
starting study drug

- Congestive heart failure (CHF) New York (NY) Heart Association class 3 or 4

- Inability to swallow or absorb drug

- Other medical or psychiatric illness or organ dysfunction or laboratory abnormality
which in the opinion of the investigator would compromise the patient's safety or
interfere with data interpretation

- Unwillingness or inability to comply with the protocol

- Pregnant

- nursing (lactating)

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, UNLESS they are using highly effective methods of contraception
during dosing and for 3 months after midostaurin medication; highly effective
contraception methods as follows:

- Total abstinence, when this is in line with the preferred and usual lifestyle of
the subject [periodic abstinence (eg, calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception]

- Female sterilization (surgical bilateral oophorectomy with or without
hysterectomy; or tubal ligation at least six weeks before taking study
treatment). In case of oophorectomy alone, reproductive status must be confirmed
by follow-up hormone level assessment

- Male sterilization, at least 6 months prior to screening (for female subjects on
the study, the vasectomized male partner should be the sole partner for that
subject)

- Combination of any two of the following (a+b or a+c, or b+c):

- Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure
rate < 1%), eg, hormone vaginal ring or transdermal hormone contraception.
For oral contraception, women should have been stable on the same pill for a
minimum of 3 months before taking study treatment

- Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository